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Anti-CD20-interleukin-21 fusokine targets malignant B cells via direct apoptosis and NK-cell–dependent cytotoxicity

Shruti Bhatt, Salma Parvin, Yu Zhang, Hyun-Mi Cho, Kranthi Kunkalla, Francisco Vega, John M. Timmerman, Seung-Uon Shin, Joseph D. Rosenblatt and Izidore S. Lossos

Key Points

  • Delivering IL-21 to tumor B cells by fusion with anti-CD20 antibody (αCD20-IL-21 fusokine) is a potent antilymphoma therapeutic strategy.

  • αCD20-IL-21 fusokine demonstrated superior antilymphoma activity compared with its individual components.

Publisher's Note: There is an Inside Blood Commentary on this article in this issue.

Abstract

In spite of newly emerging therapies and the improved survival of patients with non-Hodgkin lymphoma (NHL), relapses or primary refractory disease are commonly observed and associated with dismal prognosis. Although discovery of the anti-CD20 antibody rituximab has markedly improved outcomes in B-cell NHL, rituximab resistance remains an important obstacle to successful treatment of these tumors. To improve the efficacy of CD20-targeted therapy, we fused interleukin 21 (IL-21), which induces direct lymphoma cytotoxicity and activates immune effector cells, to the anti-CD20 antibody (αCD20-IL-21 fusokine). We observed substantially enhanced IL-21R-mediated signaling by the fusokine compared with native IL-21 at equimolar concentrations. Fusokine treatment led to direct apoptosis of lymphoma cell lines and primary tumors that otherwise were resistant to native IL-21 treatment. In addition to direct cytotoxicity, the fusokine enhanced NK cell activation, effector functions, and interferon γ production, resulting in greater antibody-dependent cell-mediated cytotoxicity compared with IL-21 and/or anti-CD20 antibody treatments. Further, the αCD20-IL-21 fusokine stabilizes IL-21 and prolongs its half-life. In vivo αCD20-IL-21 therapy resulted in a significant tumor control in the rituximab-resistant A20-huCD20 tumors. Collectively, the dual functional ability of the αCD20-IL-21 fusokine to induce direct apoptosis and activate immune effector cells may provide benefit over existing treatments for NHL.

  • Submitted September 5, 2016.
  • Accepted January 18, 2017.
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